Host recognition of bacteria by specific pattern-recognition receptors (PRRs), including Nod proteins and Toll-like receptors (TLRs), initiates antibacterial defense mechanisms and modulates the homeostasis of host-bacterial interactions. The deficiency of immune recognition results in high susceptibility of the host to infection by pathogenic bacteria. The oral cavity harbors an abundant and diverse community of bacteria, some of which have been implicated as etiological agents of common diseases such as dental caries and periodontitis. Epithelial cells lining the oral cavity and gingival tissue are known to be involved in immune responses against bacterial challenge including the production of antimicrobial peptides. However, the mechanisms by which host cells detect oral bacteria and induce antibacterial responses are largely unknown. The goal of this proposal is to test the hypothesis that Nod proteins and TLRs sense and regulate the development and maintenance of the oral microflora and the immune response to pathogenic bacteria including P. gingivalis. Preliminary results demonstrate that mice lacking PRR signaling contains oral microflora different from that of wild-type mice, suggesting that PRRs mediate selective elimination of commensal and/or pathogenic bacteria. We find that the activity of bacteria to stimulate Nod/TLR is highly diverse among bacterial species with commensal bacteria exhibiting low stimulatory activity. Thus, we hypothesize that PRRs, specifically Nod1/ Nod2, affect microflora development and pathogenic bacteria in oral cavity through host immune responses. Furthermore, we hypothesize that the oral microflora controls the susceptilibity of the host to P. gingivalis via PRR signaling. In this proposal, we propose biochemical and genetic studies to test our hypotheses and to understand the role of PRRs in the regulation of oral microflora development. These studies will provide novel insight into the mechanisms that govern the susceptibility of the host to infection by oral pathogens which may lead to the development of novel therapies for oral diseases.The human oral cavity has a complex, diverse and dynamic microflora harboring >700 cultivable and non-cultivable bacterial species. Oral bacteria colonize the surface of teeth, prostheses, gums and tongue by forming biofilm, an organized community of microbes in which microbial organisms highly interact with each other. Some bacteria are known to be involved in oral diseases; for example, Streptococcus mutans and related species in dental caries and Porphymonas gingivalis in adult periodontitis. In addition, oral bacteria have been also linked to other types of human disease including endocarditis. Oral bacteria are also involved in oral diseases through their interaction with pathogenic bacteria. Therefore, the current approach for dental diseases is not only to eliminate particular pathogenic bacteria, but also to promote bacterial populations that prevent colonization of pathogenic bacterial communities. However, the development of oral microflora in the normal state and oral diseases is largely unknown. Furthermore, studies on the control of microflora by host microbial sensing receptors have not been performed and thus the proposed studies will provide a novel concept about how hosts control the development and homeostasis of both beneficial and pathogenic microflora. The outcome of these studies is expected to provide novel insight not only into the interaction between microbial sensing receptors and commensal bacteria, but also into the role of host receptors and the microflora in periodontitis which is critical for the development of novel and improved therapies for the disease.